Description: The pathogenesis of cell death in ALS is unknown, but there is substantial evidence that both mitochondrial dysfunction and oxidative damage are involved in the process. This study will use an improved method to measure 8-hydroxy-2-deoxyguanosine (8-OH-dG), a marker of oxidative damage to DNA, in urine, plasma and CSF. The PL will now examine concentrations of 8- OH-dG in patients with both sporadic ALS, as well as in patients with specific gene mutations associated with ALS. He will determine if concentrations of 8- OH-dG change with the course of the illness. He will also sequence mitochondrial DNA (mtDNA) from postmortem tissue of ALS patients to determine if there are polymorphisms that increase the risk of ALS or if there is increased mtDNA damage which could be a consequence of oxidative damage. He will then correlate any changes in mtDNA with the concentrations of OHadG in postmortem cerebral cortex from the same patients. The investigative team will also determine if there are changes in mtDNA in transgenic mice with the G93A SOD1 mutation. They will also examine markers of oxidative damage in two transgenic mouse models of ALS associated with Cu, Zn superoxide dismutase (SOD1) mutations. They will examine mice with the G93A and the G85R SOD1 mutations which show very disparate pathologic changes. They will examine mice both for biochemical and immunohistochemical indices of oxidative damage at various time points and correlate changes with both behavioral changes, cell loss and mitochondrial changes. They will measure mitochondrial membrane potential and markers of oxidative damage in neuronal cultures from transgenic ALS mice with the G93A and G85R mutations. Lastly, they will determine if creatine and coenzyme Q10, which can improve survival in transgenic mice with the G93A SODI mutation, also improve survival in transgenic ALS mice with the G85R SOD1 mutation, and if there are additive neuroprotective effects when the two compounds are administered together. These studies are designed to determine the role of mitochondrial dysfunction in the pathogenesis of ALS and help develop new therapies for treating ALS patients.